FTY720 (Fingolimod) Sensitizes Prostate Cancer Cells to Radiotherapy by Inhibition of Sphingosine Kinase-1

Pchejetski, Dimitri; Böhler, Torsten; Brizuela, Leyre; Sauer, Lysann; Doumerc, N.; Golzio, Muriel; Salunkhe, Vishal A.; Teissié, Justin; Malavaud, Bernard; Waxman, Jonathan; Cuvillier, Olivier

doi:10.1158/0008-5472.can-10-1388

Cited by 134 publications

(166 citation statements)

References 41 publications

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“…Fingolimod (FTY720), an orally active sphingosine inhibitory analogue that we have utilized, was developed to target this pathway, and has recently been approved for use in multiple sclerosis patients to reduce the rate of relapses, presumably by preventing lymphocyte egress from lymphoid organs (36,37). The potential clinical utility of FTY720 is not limited to multiple sclerosis; Pchetski and colleagues previously demonstrated that FTY720 radiosensitizes PC3 and DU145 prostate cancer cells (38). Although our results seem to be at odds with their report, because we only observed radiosensitization of PC3-miR-95 overexpressing cells and not PC3-control cells, this discrepancy may be because of the lower concentration of FTY720 used in our study (0.5 mmol/L) compared with their study (1 mmol/L).…”

Section: Discussionmentioning

confidence: 99%

miRNA-95 Mediates Radioresistance in Tumors by Targeting the Sphingolipid Phosphatase SGPP1

et al. 2013

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Radiation resistance poses a major clinical challenge in cancer treatment, but little is known about how microRNA (miR) may regulate this phenomenon. In this study, we used next-generation sequencing to perform an unbiased comparison of miR expression in PC3 prostate cancer cells rendered resistant to fractionated radiation treatment. One miR candidate found to be upregulated by ionizing radiation was miR-95, the enforced expression of which promoted radiation resistance in a variety of cancer cells. miR-95 overexpression recapitulated an aggressive phenotype including increased cellular proliferation, deregulated G 2 -M checkpoint following ionizing radiation, and increased invasive potential. Using combined in silico prediction and microarray expression analyses, we identified and validated the sphingolipid phosphatase SGPP1, an antagonist of sphingosine-1-phosphate signaling, as a target of miR-95 that promotes radiation resistance. Consistent with this finding, cell treatment with FTY720, a clinically approved small molecule inhibitor of S1P signaling, sensitized miR-95 overexpressing cells to radiation treatment. In vivo assays extended the significance of these results, showing that miR-95 overexpression increased tumor growth and resistance to radiation treatment in tumor xenografts. Furthermore, reduced tumor necrosis and increased cellular proliferation were seen after radiation treatment of miR-95 overexpressing tumors compared with control tumors. Finally, miR-95 expression was increased in human prostate and breast cancer specimens compared with normal tissue. Together, our work reveals miR-95 expression as a critical determinant of radiation resistance in cancer cells. Cancer Res; 73(23); 6972-86. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 99%

miRNA-95 Mediates Radioresistance in Tumors by Targeting the Sphingolipid Phosphatase SGPP1

et al. 2013

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“…Concordant studies have shown that SphK1, responsible for S1P synthesis, is instrumental to cancer promotion, progression, and resistance to treatment in vitro and in vivo, notably in prostate cancer (9,19,21,22,31). In complement to preclinical literature, we recently reported the relationship between increased SphK1 activity and relevant clinical features in human prostate cancer resection specimens confirming a central role for the SphK1/ S1P signaling in prostate cancer (7).…”

Section: Discussionmentioning

confidence: 99%

“…The protocols for measurement of ceramide, sphingosine, and S1P have been described in detail previously (9,26).…”

Section: Sphk1 and Serine Palmitoyltransferase Activitiesmentioning

confidence: 99%

“…In addition, recent findings obtained on tumor tissues from patients indicate that SphK1 represents a potential prognostic marker and a viable target for therapy (6), including in prostate cancer (7). The reduction of S1P levels by SphK1 inhibition increases the efficacy of chemotherapy and radiotherapy (8,9), whereas addition of exogenous S1P protects cancer (3) and noncancer cells (10). Surprisingly, little attention has been paid to the S1P lyase (SPL), the sole enzyme that can decrease levels of intracellular S1P by irreversible cleavage into hexadecenal and ethanolamine phosphate (11).…”

Section: Introductionmentioning

confidence: 99%

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First Evidence of Sphingosine 1-Phosphate Lyase Protein Expression and Activity Downregulation in Human Neoplasm: Implication for Resistance to Therapeutics in Prostate Cancer

Brizuela

Ader

Mazerolles

et al. 2012

Molecular Cancer Therapeutics

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This is the first report of sphingosine 1-phosphate lyase (SPL) protein expression and enzymatic activity in human neoplasm. This enzyme drives irreversible degradation of sphingosine 1-phosphate (S1P), a bioactive lipid associated with resistance to therapeutics in various cancers, including prostate adenocarcinoma. In fresh human prostatectomy specimens, a remarkable decrease in SPL enzymatic activity was found in tumor samples, as compared with normal adjacent tissues. A significant relationship between loss of SPL expression and higher Gleason score was confirmed in tissue microarray (TMA) analysis. Moreover, SPL protein expression and activity were inversely correlated with those of sphingosine kinase-1 (SphK1), the enzyme producing S1P. SPL and SphK1 expressions were independently predictive of aggressive cancer on TMA, supporting the relevance of S1P in prostate cancer. In human C4-2B and PC-3 cell lines, silencing SPL enhanced survival after irradiation or chemotherapy by decreasing expression of proteins involved in sensing and repairing DNA damage or apoptosis, respectively. In contrast, enforced expression of SPL sensitized cancer cells to irradiation or docetaxel by tilting the ceramide/S1P balance toward cell death. Interestingly, the S1P degradation products failed to sensitize to chemo-and radiotherapy, supporting the crucial role of ceramide/ S1P balance in cancer. Of note, the combination of SPL enforced expression with a SphK1 silencing strategy by further decreasing S1P content made prostate cancer cells even more sensitive to anticancer therapies, suggesting that a dual strategy aimed at stimulating SPL, and inhibiting SphK1 could represent a future approach to sensitize cancer cells to cancer treatments.

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“…This drug is currently available for the treatment of multiple sclerosis (28) and has showed anticancer properties in different models of human cancers (8,29,30). This agent moderately inhibits survival of all cell lines, with an IC 50 !…”

Section: Sphk1 Inhibition Partially Restores Sensitivity To Cetuximabmentioning

confidence: 99%

Sphingosine Kinase 1 Overexpression Contributes to Cetuximab Resistance in Human Colorectal Cancer Models

Rosa

Marciano

Malapelle

et al. 2013

Clinical Cancer Research

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Purpose: Although the anti-EGF receptor (EGFR) monoclonal antibody cetuximab is an effective strategy in colorectal cancer therapy, its clinical use is limited by intrinsic or acquired resistance. Alterations in the "sphingolipid rheostat"-the balance between the proapoptotic molecule ceramide and the mitogenic factor sphingosine-1-phosphate (S1P)-due to sphingosine kinase 1 (SphK1) overactivation have been involved in resistance to anticancer-targeted agents. Moreover, cross-talks between SphK1 and EGFR-dependent signaling pathways have been described.Experimental design: We investigated SphK1 contribution to cetuximab resistance in colorectal cancer, in preclinical in vitro/in vivo models, and in tumor specimens from patients.Results: SphK1 was found overexpressed and overactivated in colorectal cancer cells with intrinsic or acquired resistance to cetuximab. SphK1 contribution to resistance was supported by the demonstration that SphK1 inhibition by N,N-dimethyl-sphingosine or silencing via siRNA in resistant cells restores sensitivity to cetuximab, whereas exogenous SphK1 overexpression in sensitive cells confers resistance to these agents. Moreover, treatment of resistant cells with fingolimod (FTY720), a S1P receptor (S1PR) antagonist, resulted in resensitization to cetuximab both in vitro and in vivo, with inhibition of tumor growth, interference with signal transduction, induction of cancer cells apoptosis, and prolongation of mice survival. Finally, a correlation between SphK1 expression and cetuximab response was found in colorectal cancer patients.

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FTY720 (Fingolimod) Sensitizes Prostate Cancer Cells to Radiotherapy by Inhibition of Sphingosine Kinase-1

Cited by 134 publications

References 41 publications

miRNA-95 Mediates Radioresistance in Tumors by Targeting the Sphingolipid Phosphatase SGPP1

miRNA-95 Mediates Radioresistance in Tumors by Targeting the Sphingolipid Phosphatase SGPP1

First Evidence of Sphingosine 1-Phosphate Lyase Protein Expression and Activity Downregulation in Human Neoplasm: Implication for Resistance to Therapeutics in Prostate Cancer

Sphingosine Kinase 1 Overexpression Contributes to Cetuximab Resistance in Human Colorectal Cancer Models

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